An oral delivery system that can precisely target drugs to the colon without prematurely delivering drugs to the upper GI tract is important and advantageous in a number of ways. Such a delivery system can be used to more effectively treat local bowel disease such as ulcerative colitis, because it minimizes systemic absorption through the upper GI tract and by so doing, maximizes the amount of drug delivered to the colon. Also, by using such delivery system, enema dosage forms, which are often impractical, and are ineffective for delivering drug to the ascending colon, may be avoided.
For drugs that are absorbed through the colon, e.g., proteins and peptide drugs, such delivery system can be used to maximize overall systemic absorption of these drugs. By avoiding exposure of the protein or peptide drugs to the upper GI tract, intraluminal degradation and breakdown of the drug can be eliminated to a large extent. Furthermore, the longer transit time for drugs in the colon (17-24 hrs) compared to the small intestine (3-4 hrs) will tend to improve overall systemic absorption of these protein or peptide drugs (1).
Oral delivery systems designed to deliver drugs to the colon are known. Dew et al (2) introduced the concept of enteric coating to target the drugs to the colon. Dew et al. reported use of an acrylic based resin (Eudragit-S.RTM., Rohm Pharm. Co., Ltd) to coat 5-amino salicylic acid or steroids as a means to deliver these drugs to the colon. Eudragit-S.RTM., a widely used enteric coating to produce acid resistant formulations, proved to be reasonably effective in achieving release of drug in the ascending colon when used at a thickness of 95-135 .mu.m. However, Eudragit S.RTM. dissolves above pH 7.0. Since the small intestinal pH is variable and can occasionally exceed pH 7.0, enteric coating alone can lead to premature dissolution of the drug in the small intestine and therefore does not provide a predictable and precise colon-targeted delivery system.
Saffran et al (3) reported the use of azopolymers (i.e. polymers cross-linked with azo-aromatic groups) for colonic delivery. These are degraded by colonic bacterial azo-reductase activity but are unaffected by gastric enzymes, and therefore were proposed as potential coatings for colonic delivery systems. These coatings are not ideal for a colon targeted delivery system, since release of drug depends on the presence of colonic anaerobic bacteria. Since the flora of anaerobic bacteria in the colon is variable, these polymers provide inconsistent drug delivery to the colon. Also, the safety of these polymeric coating materials is not completely established.
An oral delivery system based on a time-controlled explosion mechanism is described by Ueda et al., U.S. Pat. No. 4,871,549. The formulations described by Ueda et al represent a core of active ingredient and swelling agents encased by a single insoluble membrane. When this formulation is exposed to gastrointestinal fluid, the core swells and eventually bursts the encasing membrane. Ueda's system is not ideal for use as a colon-targeted delivery system since the swelling of the core begins as soon as the formulation reaches the stomach. Hence, variation in transit time through stomach will alter the site of drug delivery. Ueda discloses that the release profile of drug depends upon the properties of the core; that is, the type and amount of swelling agents, the ratio of drug to swelling agent, and whether the drug and swelling agent is layered or combined together. The release of drug using Ueda's system is not disclosed as being dependent on the composition or functional properties of the encasing insoluble membrane. In addition, Ueda, et al does not disclose any particular membrane that would burst consistently after 4-6 hours intestinal transit time or would provide for a consistent delivery of drug to the colon.
A delivery system for specifically targeting the colon is described by lamartino et al in U.S. Pat. No. 5,171,580 (5). This delivery system consists of a core of active ingredient surrounded by three layers: an outer enteric coating, a middle gelling polymer layer which swells when exposed to the enteric juice, and an anionic copolymer inner layer which is soluble at a pH above 7.0. The outer enteric coat is designed to readily dissolve upon reaching the small intestine. The middle polymer layer is designed to swell and form a protective layer for the inner anionic layer and core for about 2-4 hours while the layered dosage form transits the small intestine. After 2-4 hours, the protective layer disintegrates followed by complete disintegration of the inner anionic layer. Subsequently, there is dissolution of the core and release of active ingredient at about the time the formulation reaches the colon.
Iamartino's system has a number of disadvantages for use as a colon-targeted delivery system. First, the high viscosity grade polymer used as the middle gelling polymer layer may cause cracking or breakdown of the outer enteric coating, resulting in leakage of gastric fluid through the enteric coating and premature dissolution of drug in the small intestine. This system also provides for variable and imprecise drug delivery to the colon due to the variable lag time associated with swelling of the polymer, and disintegration of the inner anionic coating. Under these circumstances it is possible for the tablet to reach the colon prior to complete dissolution of the polymer thus diminishing exposure of the drug to the colonic environment.
A system is proposed in this invention which combines a time-dependent explosion approach and enteric coating to achieve precise and predictable delivery of drug only to the colon. This precision and predictability is in part achieved by selecting a combination of an acid resistant semi-permeable membrane of a polymer containing a plasticizer and a swellable core which will cause the membrane to burst consistently after 4-6 hours exposure to small intestinal fluid.